Control of the proliferation versus meiotic development decision in theC. elegansgermline through regulation of GLD-1 protein accumulation

Abstract

Maintenance of the stem cell population in the C. elegans germline requires GLP-1/Notch signaling. We show that this signaling inhibits the accumulation of the RNA binding protein GLD-1. In a genetic screen to identify other genes involved in regulating GLD-1 activity, we identified mutations in the nos-3 gene, the protein product of which is similar to the Drosophila translational regulator Nanos. Our data demonstrate that nos-3 promotes GLD-1 accumulation redundantly with gld-2,and that nos-3 functions genetically downstream or parallel to fbf, an inhibitor of GLD-1 translation. We show that the GLD-1 accumulation pattern is important in controlling the proliferation versus meiotic development decision, with low GLD-1 levels allowing proliferation and increased levels promoting meiotic entry.

Caenorhabditis elegans germ line: A model for stem cell biology

“…The GLD-1 and GLD-2 pathways are not only redundant for meiotic entry, they also interact, forming a complex genetic regulatory network. The data support a general model whereby the outcome of the activated GLP-1 pathway interferes with the accumulation of GLD-1 protein thereby preventing meiotic entry in the distal part of the zone (Hansen et al 2004b). The pumilio-related proteins FBF-1 and FBF-2 are required redundantly for late larval and adult maintenance of the proliferative zone and mediate the effect of the GLP-1 pathway on GLD-1-dependent meiotic entry (Crittenden et al, 2002;Lamont et al, 2004).…”

“…D: "The intensity function from the large data set with 95% confidence intervals (dashed lines) for the wild-type (blue) plus the selected glp-1(ar202) mutants (red)." E: "The wild-type intensity profile from D overlaid with the approximate steady-state protein concentration levels estimated from previous publications (Crittenden et al, 1994;Jones et al, 1996;Hansen et al, 2004b;Lamont et al, 2004). For GLP-1, we depict the region of high penetrance of high-level cell membrane-associated protein only; significant levels of internal GLP-1 are present in the germ line proximal to CD 12 (see Crittenden et al, 1994, Figs.…”

“…Genetic evidence suggests that at least one additional pathway is required to prevent meiotic entry in response to GLP-1 (Hansen et al, 2004a). Several additional genes have been tied to these two pathways, including the nanos-related gene nos-3 that acts upstream of gld-1 for meiotic entry (Hansen et al, 2004b); and atx-2, an ataxin-2 ortholog that promotes germline proliferation downstream of gld-1 and gld-2 or in parallel with GLP-1 signaling (Maine et al, 2004;Ciosk et al, 2004). Of interest, the fbfs, nos-3, gld-1, gld-2, and gld-3 are all also implicated in germline sex determination, suggesting that control of proliferation and sex determination may be linked (see Ellis and Schedl, 2006;Kimble and Crittenden, 2007).…”

“…The steady-state levels of several proteins known to affect the position of the proliferative zone border are nonuniform across the proliferative zone, including GLP-1, FBF-1, FBF-2, and GLD-1 (Hansen et al, 2004b;Lamont et al, 2004;Crittenden et al, 2006;Fig. 5).…”

“…The steady-state protein expression profile of these cells includes high levels of membrane-bound GLP-1, high levels of FBF-1 and FBF-2, and increasing (although not peak) levels of GLD-1 across the subzone. In the absence of GLP-1, the level of GLD-1 protein in this zone is uniformly high, providing evidence that GLP-1 negatively regulates GLD-1 protein levels (Jones et al, 1996;Hansen et al, 2004b). This subzone also includes a high level of germline-internalized LAG-2::betaGal(intra) protein (Henderson et al, 1994).…”